In the last six years a large number of studies have together established the notion of central or hypothalamic control of bone mass. In particular our laboratory has shown that leptin inhibits bone formation via, at least in part, a central relay and exerts both positive and negative influence on bone resorption also through a central relay. Following the identification of the sympathetic nervous system as the mediator of leptin inhibition of bone formation we have shown that the molecular clock mediates sympathetic bone in osteoblast and prevents osteoblast proliferation. The transcription factors implicated in this process are CREB and c-myc. We have also shown that downstream of leptin the sympathetic favors bone resorption while the neuropeptide CART prevents it. These observations raised questions about the role of CREB and c-myc in the mediation of the sympathetic regulation of bone formation and about the importance and mode of action of CART. We propose in the present application a combination of genetic and molecular studies to establish firmer molecular bases to the central control of bone mass. To achieve this goal we propose the following specific aims: - To demonstrate formally that the high bone mass phenotype of the Mc4r-/- mice is caused by Cart overexpression. - To determine whether CART serum levels affect bone resorption. - To determine, in vivo, the role of CREB as a transcriptional mediator of the leptin-dependent sympathetic regulation of bone mass. - To establish in vivo the role of c-myc as a mediator of the clock genes regulation of bone formation.